Approximately two-thirds of plasma cholesterol in humans is transported on low-density lipoprotein (LDL) molecules. The concentration of LDL in the bloodstream is strongly correlated with the risk of developing premature heart disease to the extent that drugs are designed to lower serum LDL levels. Drugs that reduce the level of LDL in the bloodstream have been shown in numerous clinical trials to be effective in reducing the risk of developing heart disease. The most notable examples are the “statins” (e.g. Zocor, Simvastatin, Lovastatin, Atorvastatin, Pravastatin), drugs that inhibit the activity of 3-hydroxy-3-methyl-glutaryl-coenzymeA reductase, an enzyme in the cholesterol biosynthetic pathway. However, people vary in their responsiveness to these drugs. In particular, some patients with severe forms of hypercholesterolemia are not very responsive to statins or to any other known drug therapy.
An elevation in serum LDL levels can be caused by diminished clearance of LDL particles from the circulation or by increased production of LDL or both. The clearance of LDL from the circulation is largely mediated by the LDL receptor. Thus, patients with familial hypercholesterolemia, a disease caused by LDL receptor mutations, have LDL levels 8-10-fold elevated (in the homozygous form) or 2-4-fold elevated (in the heterozygous form), as compared to patients with normal LDL receptor. This observation provides strong support for the key role of the LDL receptor in LDL metabolism.
LDL particles are not directly synthesized. Rather, the liver produces very low density lipoprotein (VLDL), which is secreted into the bloodstream. While the bloodstream, VLDL is converted into LDL. This occurs through the action of lipoprotein lipase (LPL), an enzyme residing on the lumenal surface of the capillary endothelium. LPL catalyzes the hydrolysis of the triglycerides in the VLDL particle, thus shrinking the diameter of the particle and enriching it for cholesterol and cholesterol ester (cholesterol ester is not a substrate for LPL). VLDL also acquires cholesterol ester through the action of cholesterol ester transfer protein (CETP). CETP is in the bloodstream and promotes the transfer of cholesterol ester from HDL to VLDL and the reciprocal transfer of triglyceride from VLDL to HDL. Thus, the actions of LPL and CETP lead to the conversion of a triglyceride-rich particle, VLDL, to a cholesterol-rich particle, LDL.
Excessive secretion of VLDL can lead to high levels of plasma VLDL and/or high levels of plasma LDL. Overproduction of VLDL has been seen as a metabolic consequence of many mutations in the LDL receptor. In addition, a separate metabolic disorder, termed “familial combined hyperlipidemia”, also involves the overproduction of VLDL. Consequently, another strategy for dealing with disorders resulting in excessive VLDL (hypertriglyceridemia), excessive LDL (hypercholesterolemia), or both (combined hyperlipidemia) is to interfere with the production and/or secretion of VLDL.